This K02 proposal is for renewed career development support for Dr. Neal Swerdlow, to extend a period of intensive focus on his longstanding research goal: to increase our understanding of the substrates of specific mental disorders by elucidating the neural circuitry regulating aspects of behavioral plasticity in animals and humans. For over 20 years, the PI has studied functional and anatomical interactions in limbic cortico-striato-pallido-thalamic (CSPT) circuitry that regulate sensorimotor gating of the startle reflex. This proposal describes three exciting new lines of inquiry - two in laboratory animals and one in humans - that provide the focus for the next phase of his evolving career. These studies will enhance the convergence of animal and human studies of sensorimotor gating, and will thereby maximize the full power of this cross-species approach to neurobehavioral analysis. Ultimately, this work will help to delineate the functional connections within limbic CSPT circuitry and the genetic regulation of this circuitry, and will make substantive progress towards understanding the contributions of CSPT dysfunctions to the pathophysiology of certain neuropsychiatric disorders. In one line of inquiry, the PI will examine functional interactions between regions of limbic cortex and ventral striatum that regulate sensorimotor gating in rats. Prepulse inhibition (PPI) of acoustic startle will be measured in rats after surgical and pharmacological manipulations of the hippocampus, medial prefrontal cortex and nucleus acumens. These studies will test the hypothesis that changes in sensorimotor gating of the startle reflex after manipulations of the limbic cortex in rats reflect identifiable changes in dopaminergic and glutamatergic activity within the nucleus accumbens. A second line of inquiry will use strain differences in PPI sensitivity to understand the genetic regulation of CSPT circuitry in rats. A third line of inquiry will assess the dopaminergic regulation of PPI in normal humans. Bilateral eye blink startle and PPI will be measured after administration of several different dopaminergic agents, in dose-response and agonist-antagonist studies. This proposal will provide critical new information that will facilitate the design and interpretation of future studies of sensorimotor gating in psychiatric populations, and will help us to interpret sensorimotor gating abnormalities in psychiatric patients at the levels of their underlying neural and genetic substrates.